One of the major landmarks of atherosclerosis is the presence of lipid-laden marcophages. It has been demonstrated that accumulation of LDL in macrophages can occur only after LDL has been chemically modified. One physiological form of chemical alterations is oxidative modification. In spite of increasing evidence for a central role of oxidatively-modified lipoproteins in atherosclerosis, the metabolic and immune processes that modulate the levels of these modified epitopes in vivo are not understood. For instance, the paradox inherent in the public health recommendations to increase consumption of polysaturated fatty acids and the scientific evidence that polyunsaturated fatty acids are highly susceptible to oxidative modification has yet to be explained. The present research proposed to examine the effect of the stimulation of the immune response on the expression of circulating levels of autoantibodies, the catabolism of oxidatively-modified LDL and the development of atherosclerosis. Two modes of stimulation of the immune response will be examined: immunization with malondialdehyde-modified homologous LDL and supplementation of the diet with polyunsaturated fatty acids. The working hypothesis is that interactions of triglyceride-rich lipoproteins containing dietary polyunsaturated fatty acids with the lipolytic enzymes that line the endothelium are sufficient to generate oxidatively-modified epitopes in the body. At sufficiently low concentrations, this may provide the necessary stimulus for the development of autoantibodies, part of the natural defense mechanism against these damaged particles. Excessive amounts of polyunsaturated fatty acids, however, may no longer be protective. Using radiolabeled tracers, the researchers will attempt to demonstrate that. Animals with high autoantibody titers will be able to catabolize oxidatively- modified LDL very efficiently before they can cause damage to the endothelium. In summary, the researchers should be able to demonstrate and inverse relationship between autoantibody titers and disease severity in diet-induced atherosclerosis.